Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis

ABSTRACT

An improved process for the preparation of trans-6-[2-(substituted-pyrrole-1-yl)alkyl]pyran-2-ones by a novel synthesis is described where α-metalated N,N-disubstituted acetamide is converted in seven operations to the desired products, and specifically, a process for preparing (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, as well as other valuable intermediates used in the processes and prodrugs which are bioconverted to hypolipidemic and hypocholesterolemic agents and pharmaceutical compositions of the same.

This is a divisional of U.S. application Ser. No. 08/374,356 filed Jan.18, 1995, now allowed, which is a divisional of U.S. application Ser.No. 08/323,291 filed Oct. 14, 1994, now U.S. Pat. No. 5,446,054, whichis a divisional of U.S. application Ser. No. 08/243,673 filed May 16,1994, now U.S. Pat. No. 5,397,792, which is a divisional of U.S.application Ser. No. 08/135,385 filed Oct. 12, 1993, now U.S. Pat. No.5,342,952, which is a divisional of U.S. application Ser. No. 08/025,701filed Mar. 3, 1993, now U.S. Pat. No. 5,298,627.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,647,576, which is herein incorporated by reference,discloses certaintrans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones.

U.S. Pat. No. 4,681,893, which is herein incorporated by reference,discloses certain trans-6-[2-(3- or4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones.

The compounds disclosed in the above United States patents are useful asinhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoA reductase) and are thus useful hypolipidemic andhypocholesterolemic agents. Particularly valuable as hypolipidemic andhypocholesterolemic agents aretrans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamideand(2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.The aforementioned compounds have been prepared by a linear syntheticroute which employed two reactions conducted at low temperatures (-78°C.) under carefully controlled conditions. The two reactions includedthe addition of ethyl acetoacetate to an aldehyde and the reduction ofthe hydroxy ketone produced in this reaction with sodium borohydride anda trialkylborane. Although these reactions provide the target compoundsin high diastereomeric excess, they are difficult to conduct onlarge-scale and use expensive reagents which are difficult to handle.They also do not produce enantiomerically pure products. The materialsproduced by this method can be separated into enantiomerically pureproducts but the process is very expensive, time-consuming, and resultsin the loss of more than 50% of the starting material.

The aforementioned compounds have also been prepared by a linearsynthetic route which employed two reactions conducted at lowtemperatures (-78° C.) under carefully controlled conditions. The tworeactions included the addition of the dianion of(S)-1,1,2-triphenylethanediol 2-acetate to an aldehyde and from theproduct conversion to the hydroxy ketone followed by the reduction ofthe hydroxy ketone produced in this reaction with sodium borohydride anda trialkylborane. Although these reactions provide the target compoundsin high diastereomeric excess and reasonable enantiomeric excess(85:15), they are difficult to conduct on large-scale and use expensivereagents which are difficult to handle. Also, since an 85:15 ratio ofenantiomers is produced, extensive chromatography is needed to isolatethe desired enantiomer because the racemic product crystallizes leavingthe desired isomer in the oily mother liquors. Both these linearprocedures were published by Roth, et al, J Med Chem 1991;34:356-366.

The aforementioned compounds have also been prepared by a superiorconvergent route disclosed in the following U.S. Pat. Nos. 5,003,080;5,097,045; 5,103,024; 5,124,482; and 5,149,837; which are hereinincorporated by reference and Baumann K. L., Butler D. E., Deering C.F., et al, Tetrahedron Letters 1992;33:2283-2284.

One of the critical intermediates disclosed in U.S. Pat. No. 5,097,045has also been produced using novel chemistry, as disclosed in U.S. Pat.No. 5,155,251, which is herein incorporated by reference and Brower P.L., Butler D. E., Deering C. F., et al, Tetrahedron Letters1992;33:2279-2282.

The object of the present invention is an improved process for preparingthe compounds described above by using a novel synthesis incorporatingnovel intermediates synthesized using novel chemistry.

Di-lithio and di-potassio-phenylacetamide and phenyl-acetanilide werereported in 1964 to react with ketones and methyl benzoate in liquidammonia (Work S., Bryant D., Hauser C. R., J Org Chem 1964;29:722-724).

Solutions of α-sodio N,N-dimethylacetamide and some related α-sodioN,N-dialkylamides were reported in 1966 (Gassman P., Fox B., J Org Chem1966;31:982-983 and Needles H., Whitfield R. E., J Org Chem1966;31:989-990).

Solutions of α-lithio N,N-dimethylacetamide and some related α-lithioN,N-dimethylamides were reported in 1977 (Hullot P., Cuvigny T.,Larcheveque M., Normant H., Can J Chem 1977;55:266-273 and Woodbury R.P., Rathke M. W., J Org Chem 1977;42:1688-1690). These anions have beenreacted as nucleophiles with highly reactive substances such as alkylhalides (iodides and bromides), epoxides, aldehydes and ketones.Reaction of these anions with esters appear to have been neglected ornot reported. Two references to the reaction of acetamide with methylbenzoate, which proceed through the dianion of N-benzoylacetamide withmethyl benzoate, have been found that yielded N-benzoyl benzoylacetamide(Structure A) at relatively high temperatures (Wolfe J., Timitsis G., JOrg Chem 1968;33:894 and Agami C., Bull Soc Chim Fr 1968:1205). ##STR1##

We have unexpectedly and surprisingly found that while a solution ofα-lithio N,N-dimethylacetamide does not yield any detectable desiredproduct when reacted with (R) 5-cyano-3-hydroxybutyric acid alkyl esters(Formula A), solutions of α-metallo N,N-dialkylacetamide where at leastone of the N,N-dialkyl substituents is larger than methyl or theN,N-dialkyl substituents together are cyclic, react at the ester groupof (R) 5-cyano-3-hydroxybutyric acid alkyl esters (Formula A). ##STR2##

Thus, we have unexpectedly found a broad series of novel intermediatesthat can be used to synthesize the particularly valuable hypolipidemicand hypocholesterolemic agentstrans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamideand(2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.Additionally, several of these intermediates may be used as oralprodrugs of the aforementioned hypolipidemic and hypocholesterolemicagents.

SUMMARY OF THE INVENTION

Accordingly, a first aspect of the present invention is a novel processfor the preparation of a compound of Formula I ##STR3## and a dihydroxyacid and pharmaceutically acceptable salts thereof, corresponding to theopened lactone ring of a compound of Formula I

wherein R¹ is

1-naphthyl,

2-naphthyl,

cyclohexyl,

cyclohexylmethyl,

norbornenyl,

phenyl,

phenyl substituted with

fluorine,

chlorine,

bromine,

hydroxyl,

trifluoromethyl,

alkyl of from one to four carbon atoms,

alkoxy of from one to four carbon atoms, or

alkanoyloxy of from two to eight carbon atoms,

benzyl,

2-, 3-, or 4-pyridinyl, or

2-, 3-, or 4-pyridinyl-N-oxide;

R² or R³ is independently

hydrogen,

alkyl of from one to six carbon atoms,

cyclopropyl,

cyclobutyl,

cyclopentyl,

cyclohexyl,

phenyl,

phenyl substituted with

fluorine,

chlorine,

bromine,

hydroxyl,

trifluoromethyl,

alkyl of from one to four carbon atoms, or

alkoxy of from one to four carbon atoms,

cyano,

trifluoromethyl, or --CONR⁵ R⁶ where R⁵ and R⁶ are independently

hydrogen,

alkyl of from one to six carbon atoms,

phenyl,

phenyl substituted with

fluorine,

chlorine,

bromine,

cyano, or

trifluoromethyl;

R⁴ is

alkyl of from one to six carbon atoms,

cyclopropyl,

cyclobutyl,

cyclopentyl,

cyclohexyl, or

trifluoromethyl;

which comprises:

(a) reacting a compound of Formula XI ##STR4## wherein R⁷ is alkyl offrom one to ten carbon atoms with a compound of Formula X ##STR5##wherein R⁸ or R⁹ is independently alkyl of from one to ten carbon atoms,

cyclopropyl,

cyclobutyl,

cyclopentyl,

cyclohexyl,

benzyl or

phenyl or

R⁸ and R⁹ together are

--(CH₂)₄ --,

--(CH₂)₅ --,

--(CH(R¹⁰)--CH₂)₃ --,

--(CH(R¹⁰)--CH₂)₄ --,

--(CH(R¹⁰)--(CH₂)₂ --CH(R¹⁰))--,

--(CH(R¹⁰)--(CH₂)₃ --CH(R¹⁰))--,

--CH₂ --CH₂ --O--CH₂ --CH₂ --,

--CH(R¹⁰)--CH₂ --O--CH₂ --CH₂ --,

--CH(R¹⁰)--CH₂ --O--CH₂ --CH(R¹⁰)--,

wherein R¹⁰ is alkyl of from one to four carbon atoms provided R⁸ and R⁹are not both methyl; and M is zinc, magnesium, sodium, or lithium in asolvent to afford a compound of Formula IX ##STR6## wherein R⁸ and R⁹are as defined above; (b) reacting a compound of Formula IX with eithera compound of formula

    R.sub.2.sup.10 BOCH.sub.3

wherein R¹⁰ is as defined above or

    R.sub.3.sup.10 B

wherein R¹⁰ is as defined above followed by NaBH₄ in a solvent to afforda compound of Formula VIII ##STR7## wherein R⁸ and R⁹ are as definedabove; (c) reacting a compound of Formula VIII with a ketal-formingreagent of Formula VII or Formula VIIa ##STR8## wherein R¹¹ or R¹² isindependently alkyl of from one to three carbon atoms or phenyl, or

R¹¹ and R¹² are taken together as --(CH₂)_(n) --

wherein n is 4 or 5 in the presence of an acid to afford a compound ofFormula VI ##STR9## wherein R⁸, R⁹, R¹¹, and R¹² are as defined above;(d) reacting a compound of Formula VI with hydrogen in the presence of acatalyst and a solvent to afford a compound of Formula V ##STR10##wherein R⁸, R⁹, R¹¹, and R¹² are as defined above; (e) reacting acompound of Formula V with a compound of Formula IV ##STR11## whereinR¹, R², R³, and R⁴ are as defined above in a solvent to afford acompound of Formula III ##STR12## wherein R¹, R², R³, R⁴, R⁸, R⁹, R¹¹,and R¹² are as defined above;

(f) reacting a compound of Formula III with an acid in a solvent toafford a compound of Formula II ##STR13## wherein R¹, R², R³, R⁴, R⁸,and R⁹ are as defined above;

(g)

(1) hydrolyzing a compound of Formula II with a base,

(2) followed by neutralization with an acid, and

(3) dissolution and/or heating in a solvent with concomitant removal ofwater to afford a compound of Formula I;

(h) and if desired converting the resulting compound of Formula I to adihydroxy acid corresponding to the opened lactone ring of structuralFormula I by conventional hydrolysis and further, if desired convertingthe dihydroxy acid to a corresponding pharmaceutically acceptable saltby conventional means, and if so desired converting the correspondingpharmaceutically acceptable salt to a dihydroxy acid by conventionalmeans, and if so desired converting the dihydroxy acid to a compound ofFormula I by dissolution and/or heating in an inert solvent.

A second aspect of the present invention is a novel process for thepreparation of the compound of Formula I-1 ##STR14## and the dihydroxyacid and pharmaceutically acceptable salts thereof, corresponding to theopened lactone ring of the compound of Formula I-1 which comprises:

(a) reacting the compound of Formula IVa ##STR15## with a compound ofFormula V ##STR16## wherein R⁸ or R⁹ is independently alkyl of from oneto-ten carbon atoms,

cyclopropyl,

cyclobutyl,

cyclopentyl,

cyclohexyl,

benzyl, or

phenyl or

R⁸ and R⁹ together are

--(CH₂)₄ --,

--(CH₂)₅ --,

--(CH(R¹⁰)--CH₂)₃ --,

--(CH(R¹⁰)--CH₂)₄ --,

--(CH(R¹⁰)--(CH₂)₂ --CH(R¹⁰))--,

--(CH(R¹⁰)--(CH₂)₃ --CH(R¹⁰))--,

--CH₂ --CH₂ --O--CH₂ --CH₂ --,

--CH(R¹⁰)--CH₂ --O--CH₂ --CH₂ --,

--CH(R¹⁰)--CH₂ --O--CH₂ --CH(R¹⁰)--,

wherein R¹⁰ is alkyl of from one to four carbon atoms provided R⁸ and R⁹are not both methyl; and

R¹¹ or R¹² is independently alkyl of from one to three carbon atoms orphenyl, or

R¹¹ and R¹² are taken together as --(CH₂)_(n) --

wherein n is 4 or 5 in a solvent to afford a compound of Formula IIIa##STR17## wherein R⁸, R⁹, R¹¹, and R¹² are as defined above; (b)reacting a compound of Formula IIIa with an acid in a solvent to afforda compound of Formula IIa ##STR18## wherein R⁸ and R⁹ are as definedabove; (c)

(1) hydrolyzing a compound of Formula IIa with a base,

(2) followed by neutralization with an acid, and

(3) dissolution and/or heating in a solvent with concomitant removal ofwater to afford a compound of Formula I-1;

(d) and if desired converting the resulting compound of Formula I-1 to adihydroxy acid corresponding to the opened lactone ring of structuralFormula I-1 by conventional hydrolysis and further, if desiredconverting the dihydroxy acid to a corresponding pharmaceuticallyacceptable salt by conventional means, and if so desired converting thecorresponding pharmaceutically acceptable salt to a dihydroxy acid byconventional means, and if so desired converting the dihydroxy acid to acompound of Formula I-1 by dissolution and/or heating in an inertsolvent.

A third aspect of the present invention is a novel intermediate ofFormula II ##STR19## wherein R¹, R², R³, R⁴, R⁸, and R⁹ are as definedabove which is useful in the preparation of inhibitors of cholesterolbiosynthesis of Formula I.

A fourth aspect of the present invention is a novel intermediate ofFormula III ##STR20## wherein R¹, R², R³, R⁴, R⁸, R⁹, R¹¹, and R¹² areas defined above, which useful in the preparation of a compound ofFormula II, which in turn is useful in the preparation of inhibitors ofcholesterol biosynthesis of Formula I.

A fifth aspect of the present invention is a novel intermediate ofFormula V ##STR21## wherein R⁸, R⁹, R¹¹, and R¹² are as defined above,which is useful in the preparation of a compound of Formula III, whichin turn is useful in the preparation of a compound of Formula II, whichin turn is useful in the preparation of inhibitors of cholesterolbiosynthesis of Formula I.

A sixth aspect of the present invention is a novel intermediate ofFormula VI ##STR22## wherein R⁸, R⁹, R¹¹, and R¹² are as defined above,which is useful in the preparation of a compound of Formula V, which inturn is useful in the preparation of a compound of Formula III, which inturn is useful in the preparation of a compound of Formula II, which inturn is useful in the preparation of inhibitors of cholesterolbiosynthesis of Formula I.

A seventh aspect of the present invention is a novel intermediate ofFormula VIII ##STR23## wherein R⁸ and R⁹ are as defined above, which isuseful in the preparation of a compound of Formula VI, which in turn isuseful in the preparation of a compound of Formula V, which in turn isuseful in the preparation of a compound of Formula III, which in turn isuseful in the preparation of a compound of Formula II, which in turn isuseful in the preparation of inhibitors of cholesterol biosynthesis ofFormula I.

An eighth aspect of the present invention is a novel intermediate ofFormula IX ##STR24## wherein R⁸ and R⁹ are as defined above, which isuseful in the preparation of a compound of Formula VIII, which in turnis useful in the preparation of a compound of Formula VI, which in turnis useful in the preparation of a compound of Formula V, which in turnis useful in the preparation of a compound of Formula III, which in turnis useful in the preparation of a compound of Formula II, which in turnis useful in the preparation of inhibitors of cholesterol biosynthesisof Formula I.

Additionally, it has been found that the novel intermediates of FormulaII and Formula III may be used as prodrugs which can be bioconvertedfollowing oral administration to the hypolipidemic andhypocholesterolemic agents disclosed in U.S. Pat. Nos. 4,647,576 and4,681,893.

Thus, a ninth aspect of the present invention is a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula II in unit dosage form in the treatment methods mentioned above.

A tenth aspect of the present invention is a pharmaceutical compositionfor administering an effective amount of a compound of Formula III inunit dosage form in the treatment methods mentioned above.

DETAILED DESCRIPTION OF THE INVENTION

In this invention, the term "alkyl" means a straight or branchedhydrocarbon group having from one to ten carbon atoms and includes, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tertiary-butyl(1,1-dimethylethyl), n-pentyl, tertiaryamyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

"Cycloalkyl" refers to a three- to six-membered saturated hydrocarbonring and includes, for example, cyclobutyl, cyclopentyl, cyclohexyl, andthe like.

"Alkoxy" is O-alkyl in which alkyl is as defined above.

"Alkanoyloxy" is an alkyl group, as defined above, attached to acarbonyl group and thence, through an oxygen atom, to the parentmolecular residue.

"Carboalkoxy" is an alkyl group, as defined above, attached to an oxygenatom and thence, through a carbonyl group, to the parent molecularresidue.

"Norbornenyl" is a group derived by the removal of a hydrogen atom(other than at a bridgehead carbon atom) from bicyclo[2.2.1]hept-2-ene.

"Benzyl" is also known as phenylmethyl.

"Halogen" is iodine, bromine, and chlorine.

"Alkali metal" is a metal in Group IA of the periodic table andincludes, for example, lithium, sodium, potassium, and the like.

"Alkaline-earth metal" is a metal in Group IIA of the periodic table andincludes, for example, calcium, barium, strontium, and the like.

"Noble metal" is platinum, palladium, rhodium, ruthenium, and the like.

A preferred compound of Formula I prepared by the improved process ofthe present invention is one

wherein R¹ is 1-naphthyl, norbornenyl, phenyl, or phenyl substitutedwith fluorine,

chlorine,

bromine,

hydroxyl,

trifluoromethyl,

alkyl of from one to four carbon atoms,

alkoxy of from one to four carbon atoms, or

alkanoyloxy of from two to eight carbon atoms.

Also preferred is a compound of Formula I prepared by the improvedprocess of the present invention wherein R⁴ is alkyl of from one to sixcarbon atoms, cyclopropyl, or trifluoromethyl.

Particularly preferred compounds of Formula I prepared by the improvedprocess of the present invention are the following:

trans-6-[2-[2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-6[2-[2-(4-fluorophenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2-H-pyran-2-one;

trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;

trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-2-one;

trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one;

trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one;

trans-6-[2-(2-bicyclo[2.2.1]hept-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one;

trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide;

(2R)-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide;

trans-2-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-5-trifluoromethyl-1H-pyrrole-3-carboxamide;

trans-5-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-2-trifluoromethyl-1H-pyrrole-3-carboxamide;and a dihydroxy acid and pharmaceutically acceptable salts thereof,corresponding to the opened lactone ring of compounds of structuralFormula I.

As previously described, the compounds of Formula I are useful asinhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG CoA reductase) and are thus useful as hypolipidemic orhypocholesterolemic agents.

The ability of a compound of Formula II or Formula III to act as aprodrug of the hypolipidemic and hypocholesterolemic agents disclosed inU.S. Pat. Nos. 4,647,576 and 4,681,893 may be demonstrated in a standardin vivo pharmacological assay in dogs as disclosed in European PublishedPatent Application 0259068-A2.

The process of the present invention in its first aspect is a new,improved, economical, and commercially feasible method for preparing HMGCoA reductase inhibitors of Formula I. The process of the presentinvention in its first aspect is outlined in Scheme I. ##STR25##

Thus, the (R)-5-cyano-3-hydroxybutyric acid ester of Formula XI whereinR⁷ is alkyl of from one to ten carbon atoms is treated with an α-metalamide of Formula X.

wherein R⁸ or R⁹ is independently

alkyl of from one to ten carbon atoms,

cyclopropyl,

cyclobutyl,

cyclopentyl,

cyclohexyl,

benzyl, or

phenyl or

R⁸ and R⁹ together are

--(CH₂)₄ --,

--(CH₂)₅ --,

--(CH(R¹⁰)--CH₂)₃ --,

--(CH(R¹⁰)--CH₂)₄ --,

--(CH(R¹⁰)--(CH₂)₂ --CH(R¹⁰))--,

--(CH(R¹⁰)--(CH₂)₃ --CH(R¹⁰))--,

--CH₂ --CH₂ O--CH₂ --CH₂ --,

--CH(R¹⁰)--CH₂ --O--CH₂ --CH₂ --,

--CH(R¹⁰)--CH₂ --O--CH₂ --CH(R¹⁰)--,

wherein R¹⁰ is alkyl of from one to four carbon atoms provided R⁸ and R⁹are not both methyl and M is zinc, magnesium, sodium, or lithium atabout 0° C. to about -40° C. in a solvent, such as, for example, amixture of tetrahydrofuran/heptane, and the like for about 30 minutesand subsequently poured into a solution of an acid, such as, forexample, 2.2N hydrochloride acid to afford a compound of Formula IXwherein R⁸ and R⁹ are as defined above. Preferably, the reaction iscarried out at about 0° C. to about -20° C. in a mixture oftetrahydrofuran/heptane for about 30 minutes and subsequently pouredinto 2.2N hydrochloric acid.

A hydroxy ketone amide of Formula IX is treated with a borane reagent,such as, for example, a compound of formula

    R.sub.3.sup.10 B

wherein R¹⁰ is lower alkyl, for example, tributylborane in the presenceof air or a compound of formula

    R.sub.2.sup.10 BOCH.sub.3

wherein R¹⁰ is as defined above, for example, methoxydiethylborane inthe absence of air and subsequent treatment with a metal hydride, suchas, for example, sodium borohydride in a solvent, such as, for example,methanol, tetrahydrofuran, mixtures thereof, and the like at about 0° C.to about -110° C. for about 5 hours followed by subsequent treatmentwith an acid, such as, for example, glacial acetic acid, and the like toafford a compound of Formula VIII wherein R⁸ and R⁹ are as definedabove. Preferably, the reaction is carried out with methoxydiethylboraneunder a nitrogen atmosphere and subsequent treatment with sodiumborohydride in a mixture of methanol and tetrahydrofuran at about -20°C. to about -78° C. for about 5 hours followed by the addition ofglacial acetic acid.

A 3,5-dihydroxy amide of Formula VIII is treated with a ketal-formingreagent of Formula VII or Formula VIIa ##STR26## wherein R¹¹ or R¹² isindependently alkyl of from one to three carbon atoms or phenyl or

R¹¹ and R¹² are taken together as --(CH₂)_(n) -- wherein n is 4 or 5,for example, a ketal-forming reagent selected from the group consistingof acetone, 2,2-dimethoxypropane, 2-methoxypropene, cyclopentanone,cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane, andthe like or optionally an acetal forming reagent, for example,benzaldehyde, and the like in the presence of an acid, such as, forexample, methanesulfonic acid, camphorsulfonic acid, paratoluenesulfonicacid, and the like, in the presence of excess reagent or in an inertsolvent, such as, for example, dichloromethane, and the like at about 0°C. to about the reflux temperature of the reagent or solvent to afford acompound of Formula VI wherein R⁸, R⁹, R¹¹, and R¹² are as definedabove. Preferably, the reaction is carried out with a ketone formingreagent of Formula VII, for example, 2,2-dimethoxypropane and acetone inthe presence of methanesulfonic acid at about room temperature.

A compound of Formula VI is treated with hydrogen gas in an alcohol,such as, for example methanol saturated with anhydrous ammonia oraqueous ammonium hydroxide, and the like, in the presence of a catalyst,such as, for example, Raney nickel, Raney cobalt, a noble metalcatalyst, such as, for example, platinum oxide in the presence of analkanoic acid, such as acetic acid, and the like to afford a compound ofFormula V wherein R⁸, R⁹, R¹¹, and R¹² are as defined above. Preferably,the reaction is carried out with hydrogen gas in the presence of Raneynickel in methanol saturated with anhydrous ammonia.

A compound of Formula V is reacted with a diketone of Formula IV

wherein R¹ is

1-naphthyl,

2-naphthyl,

cyclohexyl,

cyclohexylmethyl,

norbornenyl,

phenyl,

phenyl substituted with

fluorine,

chlorine,

bromine,

hydroxyl,

trifluoromethyl,

alkyl of from one to four carbon atoms,

alkoxy of from one to four carbon atoms, or

alkanoyloxy of from two to eight carbon atoms,

benzyl,

2-, 3-, or 4-pyridinyl, or

2-, 3-, or 4-pyridinyl-N-oxide;

R² or R³ is independently

hydrogen,

alkyl of from one to six carbon atoms,

cyclopropyl,

cyclobutyl,

cyclopentyl,

cyclohexyl,

phenyl,

phenyl substituted with

fluorine,

chlorine,

bromine,

hydroxyl,

trifluoromethyl,

alkyl of from one to four carbon atoms, or

alkoxy of from one to four carbon atoms,

cyano,

trifluoromethyl, or --CONR⁵ R⁶ where R⁵ and R⁶ are independently

hydrogen,

alkyl of from one to six carbon atoms,

phenyl,

phenyl substituted with

fluorine,

chlorine,

bromine,

cyano, or

trifluoromethyl;

R⁴ is

alkyl of from one to six carbon atoms,

cyclopropyl,

cyclobutyl,

cyclopentyl,

cyclohexyl, or

trifluoromethyl;

in an inert solvent or mixtures thereof, such as, for example,tetrahydrofuran, heptane, toluene, and the like at about the refluxtemperature of the solvent in the presence of a catalyst of formula

    R.sup.13 CO.sub.2 H

wherein R¹³ is CH₃ --, CF₃ --, Cl--CH₂ --, Cl--CH₂ --CH₂ --, C₆ H₅ --CH₂--CH₂, C₆ H₅ --CH₂ --, HO₂ C--CH₂ --, HO₂ C--CH₂ --CH₂ --, C₆ H₅ --,para-Cl--C₆ H₅ --, para-CH₃ --C₆ H₅ --, meta-CH₃ --C₆ H₅ --, tertiary-C₄H₉ --, or triethylamine hydrochloride to give a compound of Formula IIIwherein R¹, R², R³, R⁴, R⁸, R⁹, R¹¹, and R¹² are as defined above.Preferably, the reaction is carried out inheptane/tetrahydrofuran/toluene in the presence of pivalic acid at aboutthe reflux temperature of the solvent mixture.

A compound of Formula III, a hydroxy-protected pyrrole amide, is treatedwith an acid, such as, for example, aqueous hydrochloric acid, and thelike in an inert solvent, such as, for example, tetrahydrofuran,methanol, and the like to afford a compound of Formula II wherein R¹,R², R³, R⁴, R⁷, R⁸, and R⁹ are as defined above. Preferably, thereaction is carried out in methanol in the presence of 1.0N hydrochloricacid solution.

A compound of Formula II, the beta, gammadihydroxy-pyrroleheptaneamide,is hydrolyzed with a base, such as, for example, alkali metal hydroxide,for example, sodium hydroxide or an alkaline-earth metal hydroxide in asolvent, such as, for example methanol, and the like and subsequentwashing with an inert solvent, such as, for example, toluene, methyltert-butyl methyl ether, and the like to afford a compound of Formula Ibwherein M is lithium, sodium, potassium, calcium, barium, strontium, andthe like and R¹, R², R³, and R⁴ are as defined above. Preferably, thereaction is carried out in methanol with 2.0N aqueous sodium hydroxideand subsequent washing with tert-butyl methyl ether.

Optionally, a compound of Formula Ib wherein Ma is sodium and R¹, R²,R³, and R⁴ are as defined above may be converted to a hemi-calcium saltcompound of Formula Ib by treatment with an aqueous solution of calciumacetate.

A compound of Formula Ib is treated with an acid, such as, for example,dilute aqueous hydrochloric acid and subsequently extracted into aninert solvent, such as, for example, tert-butyl methyl ether, diethylether, hexane, toluene, and the like to afford a compound of Formula Iawherein R¹, R², R³, and R⁴ are as defined above. Preferably, thereaction is carried out with 2N aqueous hydrochloric acid and subsequentextraction into tert-butyl methyl ether.

A compound of Formula Ia is dissolved and/or heated in an inert solvent,such as, for example, toluene, and the like, with or without concomitantremoval of water to afford a compound of Formula I, wherein R¹, R², R³,and R⁴ are as defined above. Preferably, the reaction is carried out bydissolving and/or heating a compound of Formula Ia in toluene at aboutreflux with azeotropic removal of water.

The process of the present invention in its second aspect is a new,improved, economical, and commercially feasible method for preparing theHMG CoA reductase inhibitor of Formula Ic. The process of the presentinvention in its second aspect is outlined in Scheme II. ##STR27##

Thus, a compound of Formula V is reacted with the compound of FormulaIVa using the methodology used to prepare a compound of Formula III froma compound of Formula V and a compound of Formula IV to afford acompound of Formula IIIa wherein R⁸, R⁹, R¹¹, and R¹² are as definedabove.

A compound of Formula IIIa is converted to a compound of Formula IIawherein R⁸, R⁹, and M are as defined above using the methodology used toprepare a compound of Formula II from a compound of Formula III.

A compound of Formula IIa is converted to a compound of Formula Ib-1wherein M is as defined above using the methodology used to prepare acompound of Formula Ib from a compound of Formula II.

A compound of Formula Ib-1 is converted to a compound of Formula Ia-1using the methodology used to prepare a compound of Formula Ia from acompound of Formula 1b.

A compound of Formula Ia-1 is converted to a compound of Formula I-1using the methodology used to prepare a compound of Formula I from acompound of Formula Ia.

The optically active 3(R) centers in compounds of Formula XI establishesthe optically active center or centers desired in Formula IX, FormulaVIII, Formula VI, Formula V, Formula III, Formula IIIa, Formula II,Formula IIa, Formula Ib, Formula Ib-1, Formula Ia, Formula Ia-1, FormulaI, and Formula I-1.

Compounds of Formula XI, Formula VII, Formula IV, Formula IVa, areeither known or capable of being prepared by methods known in the art.

The ring-opened dihydroxy acids of Formula Ia and Formula Ia-1 may beprepared from the lactone compounds of Formula I or Formula I-1,respectively, by conventional hydrolysis, such as, for example, sodiumhydroxide in methanol, sodium hydroxide in tetrahydrofuran-water, andthe like, of the lactone compounds of Formula I or Formula I-1.

In the ring-opened dihydroxy acid form, compounds of the presentinvention react to form salts with pharmaceutically acceptable metal andamine cations formed from organic and inorganic bases. The term"pharmaceutically acceptable metal salt" contemplates salts formed withthe sodium, potassium, calcium, magnesium, aluminum, iron, and zincions. The term "pharmaceutically acceptable amine salt" contemplatessalts with ammonia and organic nitrogenous bases strong enough to formsalts with carboxylic acids. Bases useful for the formation ofpharmaceutically acceptable nontoxic base addition salts of the compoundof the present invention form a class whose limits are readilyunderstood by those skilled in the art.

The dihydroxy free acid form of the compounds of the invention may beregenerated from the salt form, if desired, by contacting the salt witha dilute aqueous solution of an acid, such as hydrochloric acid.

The ring closed lactone form of the compounds of the invention may beregenerated by dissolution of the dihydroxy free acid form of thecompounds of the invention in an inert solvent such as, for example,toluene, benzene, ethyl acetate, and the like, at about 0° C. to aboutthe boiling point of the solvent usually but not necessarily withconcomitant removal of the resulting water and usually but notnecessarily with strong acid catalysis such as, for example,concentrated hydrochloric acid and the like.

The base addition salts may differ from the free acid forms of thecompounds of this invention in such physical characteristics assolubility and melting point, but are otherwise considered equivalent tothe free acid form for the purposes of this invention.

The compounds of the present invention may exist in solvated orunsolvated form and such forms are equivalent to the unsolvated form forthe purposes of this invention.

The compounds of structural Formulas I, and I-1, above possess twoasymmetric carbon centers, one at the 4-hydroxyposition of thepyran-2-one ring, and the other at the 6-position of the pyran-2-onering where the alkylpyrrole group is attached. This asymmetry gives riseto four possible isomers, two of which are the 4R,6S and 4S,6R-isomersand the other two of which are the 4R,6R and the 4S,6S-isomers. Thepreferred isomer in this invention is the 4R,6R-isomer of the compoundsof Formulas I, and I-1, above.

The compounds of Formula II or Formula III of the present invention canbe prepared and administered in a wide variety of oral forms.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, and dispersible granules. A solid carrier canbe one or more substances which may also act as diluents, flavoringagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from 5% or 10% to about 70%of the active compound. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term "preparation" isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials.Also, the unit dosage form can be a capsule, tablet, cachet, or lozengeitself, or it can be the appropriate number of any of these in packagedform.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 2.5 mg to 2000 mg preferably 5 mg to 600 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as hypolipidemic and hypocholesterolemic agents, thecompounds of Formula II or Formula III utilized in the pharmaceuticalmethod of this invention are administered at the initial dosage of about0.01 mg to about 8 mg/kg daily. A daily dose range of about 0.01 mg toabout 10 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

The following nonlimiting examples illustrates the inventors' preferredmethod for preparing the compounds of the invention. EXAMPLE 1[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt

Step 1: Preparation of(R)-6-cyano-5-hydroxy-3-oxo-N,N-diphenylhexanamide

To a stirred -10° C. solution of N,N-diphenylacetamide (211 g, 1.0 mol)in tetrahydrofuran (1.0 L) is slowly added a solution of lithiumdiisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) whilemaintaining the temperature between -10° C. to -5° C. The mixture isstirred at -0° C. to 20° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyricacid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200mL of tetrahydrofuran is added to the previously prepared anion. Thereaction mixture is stirred for 30 minutes at -5° C. to -20° C., andtransferred to a 2.2N aqueous hydrochloric acid solution (1 L). Theaqueous layer is extracted with 500 mL of ethyl acetate, the aqueouslayer is separated and reextracted with 100 mL of ethyl acetate, theextracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-5-hydroxy-3-oxo-N,N-diphenylhexanamide which is not isolated. Asmall sample is purified by column chromatography on flash silica gel(60:40 hexane:ethyl acetate) as an oil. Proton nuclear magneticresonance spectroscopy

(¹ H-NMR): (Acetone-d₆) δ2.02 (m, 2H), 2.73 (m, 2H), 4.1 (m, 2H), 4.52(m, 1H), 4.74 (s, 1H), 7.2-7.4 (m, 10H). Molecular weight: 322. GasChromatography/Mass Spectroscopy (GC/MS) m/e 322, 169, 154, 141, 128,115, 77, 65, 51, 39, 32.

Step 2: Preparation of[R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide

Crude (R)-6-cyano-5-hydroxy-3-oxo-N,N-diphenylhexanamide, approximately0.2 mol, is dissolved in tetrahydrofuran (200 mL) and methanol (100 mL)under a nitrogen atmosphere. The solution is cooled to -20° C., and a50% solution of methoxydiethylborane in tetrahydrofuran (105 mL) isadded. The reaction is cooled to -78° C., and sodium borohydride (24 g,0.63 mol) is added over 30 minutes. The reaction mixture is maintainedat -78° C. for 5 hours, allowed to warm to room temperature, and standfor 10 hours under a nitrogen atmosphere. The reaction is quenched bythe addition of acetic acid (40 mL) and concentrated by vacuumdistillation to an oil. The residue is dissolved with methanol (400 mL),concentrated by vacuum distillation, redissolved with methanol (300 mL),and reconcentrated by vacuum distillation to give a yellow oil. The oilis taken up in ethyl acetate (300 mL) and washed with deionized water(500 mL). The ethyl acetate solution is concentrated by vacuumdistillation to give[R-(R*,R*)])-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide as an oilwhich is used without further purification. A small sample is purifiedby column chromatography on flash silica gel (60:40 hexane:ethylacetate) as an oil.

¹ H-NMR:(CDCl₃) δ1.6 (m, 2H), 2.4 (m, 2H), 2.5 (m, 2H), 4.1 (m, 1H), 4.2(m, 1H), 4.4 (s, 1H), 4.8 (s, 1H), 7.1→7.5 (m, 10H) . Molecular weight:324. GC/MS m/e 324, 307, 284, 266, 240, 212, 186, 170, 158, 130, 112.

Step 3: Preparation of(4R-cis)-6-(cyanomethyl)-2.2-dimethyl-N,N-diphenyl-1.3-dioxane-4-acetamide

Crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide,approximately 0.18 mol, is dissolved in 2,2-dimethoxypropane (160 mL,1.5 mol) and acetone (300 mL). Methanesulfonic acid (0.5 mL) is added,and the solution is stirred for 2 hours at room temperature. Thereaction is quenched by the addition of aqueous sodium bicarbonate (800mL) and ethyl acetate (500 mL). The ethyl acetate solution isconcentrated by vacuum distillation to give 62.5 g of(4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamideas an off-white crystalline solid (mp 98°-100° C., uncorrected).

¹ H-NMR (CDCl₃) δ1.37 (s, 3H), 1.46 (s, 3H), 1.82 (d, 1H, J=13 Hz), 2.33(dd, 1H, J=16, 6H), 2.48 (d, 1H, J=6 Hz), 2.60 (dd, 1H, J=16, 6 Hz),4.0-4.2 (m, 2H), 4.4-4.6 (m, 2H), 7.0-7.5 (m, 10H) . Molecular weight:364. GC/MS m/e 364, 349, 307, 289, 196, 169, 154, 138, 93, 77, 59, 43.

Step 4: Preparation of(4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide

A solution of(4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide(10.0 g, 0.027 mol) in methanol (150 mL) containing anhydrous ammonia(2.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in thepresence of a slurry of Raney nickel A-7000 (3.8 g). After 3 hours,uptake of hydrogen has ceased, the mixture is cooled to 20° C., theatmosphere is vented and exchanged for nitrogen, the slurry is filteredthrough celite, and concentrated at reduced pressure to give 9.5 g of(4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamideas an oil.

¹ H-NMR (DMSO) δ1.23 (s, 3H), 1.37 (s, 3H), 2.29 (m, 1H), 2.33 (m, 1H),2.36 (m, 2H), 2.49 (m, 2H), 2.50 (m, 2H), 3.01 (m, 2H), 3.22 (s, 2H),7.37 (s, 10H).

Step 5: Preparation of(4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide

A nitrogen purged 500 mL three-neck flask is charged with4-fluoro-α-(2-methyl-1-oxopropyl)-γ-oxo-N,β-diphenylbenzenebutanamide(Baumann, supra) (13.6 g, 0.032 mol),(4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide(10.0 g, 0.027 mol), heptane (100 mL) , pivalic acid (3 g),tetrahydrofuran (50 mL), and toluene (60 mL). The mixture is heated toreflux for 48 hours, cooled to room temperature, and diluted withtoluene (300 mL). The solution is washed with 0.5N aqueous sodiumhydroxide (150 mL), followed by 0.5N aqueous hydrochloric acid (250 mL),and concentrated by vacuum distillation to a foam. The product,(4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide,is used in the next step without further purification. Fourier TransformInfrared Spectroscopy (FTIR)(KBr) 3450, 2860, 1650, 1620 cm⁻¹ ;

¹ H-NMR (DMSO) δ1.27 (s, 3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.72 (s, 3H),2.05 (m, 1H), 2.47 (m, 1H), 3.25 (m, 2H), 3.27 (m, 2H), 3.29 (m, 2H),3.32 (s, 1H), 3.32 (s, 1H), 7.0-7.4 (m, 24H).

Step 6: Preparation of[R-(R*,R*)]-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide

(4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamideis dissolved in methanol (300 mL) and reacted by adding 1.0Nhydrochloric acid (100 mL) and stirring for 12 hours at roomtemperature. The white crystalline solid[R-(R*,R*)]-5-(4-fluorophenyl)-β,γ-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamideis isolated by filtration (mp 228.5°-232.9° C., uncorrected). FTIR (KBr)3400 (broad), 2850, 1640 cm⁻¹ ;

¹ H-NMR (CDCl₃) δ1.50 (m, 1H), 1.54 (m, 1H), 1.8-1.95 (s, 6H), 2.0-2.17(m, 8H), 3.70 (s, 1H), 7.1-7.4 (m, 24H), 11.16 (s, 2H).

Step 7: Preparation of[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, sodium salt

A nitrogen purged 500 mL three-neck flask is charged with[R-(R*,R*)]-5-(4-fluorophenyl)-β,δ-dihydro-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide(4.0 g, methanol (30 mL), and 2.0N aqueous sodium hydroxide (60 mL). Themixture is heated to 70° C. for 4 hours and cooled to room temperature.A white solid is filtered and discarded. The filtrate is washed withtert-butyl methyl ether, and the aqueous layer is acidified to a pH of 2by the addition of 2N aqueous hydrochloric acid and extracted withtert-butyl methyl ether. The organic layer is separated, mixed withwater (200 mL), methanol (20 mL), and brought to a pH of 12 by additionof 2.0N aqueous sodium hydroxide. The aqueous layer is washed withtert-butyl methyl ether (50 mL) and water (100 mL). The aqueous layercontains the sodium salt of[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid.

Step 8: Preparation of[-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt

In a separate 200 mL beaker, calcium acetate (1.2 g, 7 mmol) isdissolved in water (20 mL). This calcium acetate solution is added to[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, sodium salt solution and stirred at room temperature for 2 hours.The resultant solution is cooled to 10° C. for about 3 hours. The whitesolid is collected by filtration, washed with cold water, and isconfirmed as[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-heptanoic,hemi calcium salt by High Performance Liquid Chromatography retentiontime comparison.

HPLC conditions:

Column: Ultramex CI8, 5u (250×4.6 mm).

Mobil phase: 22% MeCN:12% THF:66% 0.05M NH₄ H₂ PO₄ pH=5 with NH₄ OH

Flow rate: 1.5 mm/min

Detector: 254 nm

Retention time: 44.9-45.1.

EXAMPLE 2[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt

Preparation of(4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide

To a stirred -10° C. solution of N,N-bis(phenylmethyl)acetamide(prepared from N, N-bis(phenylmethyl)amine and acetyl chloride byrefluxing for 2 hours in toluene) (120 g, 0.5 mol) in tetrahydrofuran(0.5 L) is slowly added a solution of lithium diisopropylamide intetrahydrofuran-heptane (0.25 L of 2M) while maintaining the temperaturebetween -30° C. to -45° C., and the mixture is stirred at -20° C. to-30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester(Brower, supra) (20 g, 0.125 mol) as a solution in 200 mL oftetrahydrofuran is then added to the previous mixture. The reactionmixture is stirred for 30 minutes at -35° C. to -20° C., and transferredto a 2.2N aqueous hydrochloric acid solution (0.5 L). The aqueous layeris extracted with 300 mL of ethyl acetate, the aqueous layer isseparated and reextracted with 100 mL of ethyl acetate, the extracts arecombined and concentrated in vacuo to afford crude(R)-6-cyano-5-hydroxy-3-oxo-N,N-bis(phenylmethyl)hexanamide as an oil.This oil, approximately 0.1 mol, is dissolved in tetrahydrofuran (200mL) and methanol (100 mL) under a nitrogen atmosphere. The solution iscooled to -20° C., and a 50% solution of methoxydiethylborane intetrahydrofuran (50 mL) is added. The reaction is cooled to -78° C., andsodium borohydride (12 g, 0.32 mol) is added over 30 minutes. Thereaction is maintained at -78° C. for 5 hours and allowed to warm toroom temperature and stand for 10 hours under a nitrogen atmosphere. Thereaction is quenched by the addition of acetic acid (20 mL) andconcentrated by vacuum distillation to an oil. The residue is dissolvedwith methanol (300 mL), concentrated by vacuum distillation, redissolvedwith methanol (300 mL), and reconcentrated by vacuum distillation togive a yellow oil. The oil is taken up in ethyl acetate (300 mL) andwashed with deionized water (300 mL). The ethyl acetate solution isconcentrated by vacuum distillation to give crude[R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-bis(phenylmethyl)hexanamide as anoil which is used without further purification;

Molecular weight: 352. GC/MS m/e 352, 197, 179, 120, 106, 91, 77, 65,51, 39.

The crude oil, approximately 0.09 mol, is dissolved in2,2-dimethoxypropane (100 mL, 1.0 mol) and acetone (200 mL).Methanesulfonic acid (0.4 mL) is added, and the solution is stirred for2 hours at room temperature. The reaction is quenched by the addition ofaqueous sodium bicarbonate (500 mL) and ethyl acetate (300 mL). Theethyl acetate solution is concentrated by vacuum distillation to give32.1 g of(4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamideas an oil;

Molecular weight: 392. GC/MS m/e 392, 239, 196, 148, 106, 91, 79, 65,43, 32.

A solution of(4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide(10.0 g, 0.025 mol) in methanol (150 mL) containing anhydrous ammonia(2.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in apresence of a slurry of Raney nickel A-7000 (3.7 g). After 3 hours,uptake of hydrogen has ceased, the mixture is cooled to 20° C., theatmosphere is vented and exchanged for nitrogen, the slurry is filteredthrough celite, and concentrated at reduced pressure to give 9.4 g of(4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamide as an oil;

¹ H-NMR (DMSO) δ1.26 (s, 3H), 1.41 (s, 3H), 2.12 (m, 1H), 2.5 (m, 1H),3.11 (m, 2H), 3.23 (m, 2H), 3.35 (m, 2H) , 4.44 (m, 2H), 4.48 (m, 2H),4.52 (m, 4H), 7.3-7.5 (s, 10H).

In a process analogous to Example 1,(4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-bis(phenylmethyl)-1,3-dioxane-4-acetamideis converted to[R-(R*,R*)]-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-N,N-bis(phenylmethyl)-1H-pyrrole-1-heptanamidewhich is further converted to[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl-1H-pyrrole-1-heptanoicacid, hemi calcium salt.

EXAMPLE 3[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt

Preparation of (4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide

To a stirred -10° C. solution of N,N-diethylacetamide (prepared fromN,N-diethylamine and acetyl chloride by refluxing for 2 hours intoluene) (28.75 g, 0.25 mol) in tetrahydrofuran (0.25 L) is slowly addeda solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.125L of 2M) while maintaining the temperature between -10° C. to -5° C.,and the mixture is stirred at -20° C. to 0° C. for 30 minutes.(R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (10 g,0.06 mol) as a solution in 200 mL of tetrahydrofuran is added to thepreviously prepared mixture. The reaction mixture is stirred for 30minutes at -5° C. to -20° C., and transferred to a 2.2N aqueoushydrochloric acid solution (0.25 L). The aqueous layer is extracted with300 mL of ethyl acetate, the aqueous layer is separated and reextractedwith 50 mL of ethyl acetate, the extracts are combined and concentratedin vacuo to afford crude(R)-6-cyano-N,N-diethyl-5-hydroxy-3-oxohexanamide as an oil;

Molecular weight: 226. GC/MS m/e 226, 157, 140, 114, 72, 58, 32.

This oil, approximately 0.05 mol, is dissolved in tetrahydrofuran (200mL) and methanol (100 mL) under a nitrogen atmosphere. The solution iscooled to -20° C., and a 50% solution of methoxydiethylborane intetrahydrofuran (30 mL) is added. The reaction is cooled to -78° C., andsodium borohydride (6 g, 0.15 mol) is added over 30 minutes. Thereaction is maintained at -78° C. for 5 hours, allowed to warm to roomtemperature, and stand for 10 hours under a nitrogen atmosphere. Thereaction is quenched by the addition of acetic acid (10 mL) andconcentrated in vacuo to an oil. The residue is dissolved with methanol(200 mL), concentrated by vacuum distillation, redissolved with methanol(250 mL), and reconcentrated by vacuum distillation to give a yellowoil. The oil is taken up in ethyl acetate (300 mL), and washed withdeionized water (300 mL). The ethyl acetate solution is concentrated invacuo to give [R-(R*,R*)] -6-cyano-N,N-diethyl-3,5-dihydroxyhexanamideas an oil which is used without further purification;

Molecular weight: 228. GC/MS m/e 228, 168, 100, 72, 43.

The oil, approximately 0.05 mol, is dissolved in 2,2-dimethoxypropane(50 mL, 0.5 mol) and acetone (100 mL). Methanesulfonic acid (0.3 mL) isadded, and the solution is stirred for 2 hours at room temperature. Thereaction is quenched by the addition of aqueous sodium bicarbonate (300mL) and ethyl acetate (300 mL). The ethyl acetate layer is concentratedin vacuo to give 12.4 g of(4R-cis)-6-(cyanomethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamideas an oil;

Molecular weight: 268. GC/MS m/e 268, 253,210, 170, 100, 72, 43.

A solution of(4R-cis)-6-(cyanomethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamide(10.0 g, 0,037 mol) in methanol (220 mL) containing anhydrous ammonia(3.25 g) is reacted with hydrogen gas in a Parr shaker at 30° C. in apresence of a slurry of Raney nickel A- 7000 (4.2 g) . After 3 hours,uptake of hydrogen has ceased, the mixture is cooled to 20° C., theatmosphere is vented and exchanged for nitrogen, the slurry is filteredthrough celite, and concentrated at reduced pressure to give 9.2 g of(4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamideas an oil.

In a process analogous to Example 1,(4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamideis converted to[R-(R*,R*)]-N,N-diethyl-5-(4-fluorophenyl)-β,δ-5-dihydroxy-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamidewhich is further converted to[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-5-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, hemi calcium salt.

EXAMPLE 4[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt

Preparation of(4R-cis)-6-(2-aminoethyl)-N-butyl-N,2,2-trimethyl-1,3-dioxane-4-acetamide

To a stirred -10° C. solution of N,N-n-butylmethylacetamide (preparedfrom N,N-n-butylmethylamine and acetyl chloride by refluxing for 2 hoursin toluene) (65 g, 0.5 mol) in tetrahydrofuran (0.5 L) is slowly added asolution of lithium diisopropylamide in tetrahydrofuran-heptane (0.25 Lof 2M) while maintaining the temperature between -40° C. to -50° C., andthe mixture is stirred at -20° C. to -30° C. for 30 minutes.(R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (20 g,0,125 mol) as a solution in 200 mL of tetrahydrofuran is then added tothe previous mixture. The reaction mixture is stirred for 30 minutes at-25° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acidsolution (0.5 L). The aqueous layer is extracted with 300 mL of ethylacetate, the aqueous layer is separated and reextracted with 100 mL ofethyl acetate, the extracts are combined and concentrated in vacuo toafford crude (R)-N-butyl-6-cyano-5-hydroxy-N-methyl-3-oxohexanamide asan oil.

The oil, approximately 0.1 mol, is dissolved in tetrahydrofuran (200 mL)and methanol (100 mL) under a nitrogen atmosphere. The solution iscooled to -20° C., and a 50% solution of methoxydiethylborane intetrahydrofuran (50 mL) is added. The reaction is cooled to -78° C., andsodium borohydride (12 g, 0.32 mol) is added over 30 minutes. Thereaction is maintained at -78° C. for 5 hours and allowed to warm toroom temperature and stand for 10 hours under a nitrogen atmosphere. Thereaction is quenched by the addition of acetic acid (20 mL) andconcentrated in vacuo to an oil. The residue is dissolved with methanol(300 mL), concentrated by vacuum distillation, redissolved with methanol(300 mL), and reconcentrated in vacuo to give a yellow oil. The oil istaken up in ethyl acetate (300 mL) and washed with deionized water (300mL). The ethyl acetate solution is concentrated by vacuum distillationto give crude[R-(R*,R*)]-N-butyl-6-cyano-3,5-dihydroxy-N-methylhexanamide as an oilwhich is used as is.

The oil, approximately 0.1 mol, is dissolved in 2,2-dimethoxypropane(100 mL, 1.0 mol) and acetone (200 mL). Methanesulfonic acid (0.5 mL) isadded, and the solution is stirred for 2 hours at room temperature. Thereaction is quenched by the addition of aqueous sodium bicarbonate (400mL) and ethyl acetate (300 mL). The ethyl acetate solution isconcentrated by vacuum distillation to give 26.5 g of(4R-cis)-N-butyl-6-(cyanomethyl)-N,2,2-trimethyl-1,3-dioxane-4-acetamideas an oil;

Molecular weight: 282. GC/MS m/e 282, 267, 207, 184, 154, 114, 87, 57,44.

A solution of this nitrile (10.0 g, 0.035 mol) in methanol (183 mL)containing anhydrous ammonia (2.75 g) is reacted with hydrogen gas in aParr shaker at 30° C. in the presence of a slurry of Raney nickel A-7000(4.2 g). After 3 hours, uptake of hydrogen has ceased, the mixture iscooled to 20° C., the atmosphere is vented and exchanged for nitrogen,the slurry is filtered through celite, and concentrated in vacuo to give9.25 g of(4R-cis)-6-(2-aminoethyl)-N-butyl-N,2,2-trimethyl-1,3-dioxane-4-acetamideas an oil.

In a process analogous to Example 1,(4R-cis)-6-(2-aminoethyl)-N-butyl-N,2,2-trimethyl-1,3-dioxane-4-acetamideis converted to[R-(R*,R*)]-N-butyl-5-(4-fluorophenyl)-β,δ-dihydroxy-N-methyl-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamidewhich is further converted to[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1-pyrrole-1-heptanoicacid, hemi calcium salt.

EXAMPLE 5[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt

Preparation of(4R-cis)-6-(2-aminoethyl)-N-(1,1-dimethylethyl)-2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamide

To a stirred -10° C. solution of N-1,1-dimethylethyl,N-phenylmethylacetamide (prepared from N-1,1-dimethylethyl,N-phenylmethyl amine, and acetyl chloride by refluxing for 2 hours intoluene) (102.5 g, 0.5 mol) in tetrahydrofuran (0.5 L) is slowly added asolution of lithium diisopropylamide in tetrahydrofuran-heptane (0.25 Lof 2M) while maintaining the temperature between -40° C. to -50° C., andthe mixture is stirred at -20° C. to -30° C. for 30 minutes.(R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (20 g,0.125 mol) as a solution in 200 mL or tetrahydrofuran is then added tothe previous mixture. The reaction mixture is stirred for 30 minutes at-25° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acidsolution (0.5 L). The aqueous layer is extracted with 300 mL of ethylacetate, the aqueous layer is separated and reextracted with 100 mL ofethyl acetate, the extracts are combined and concentrated in vacuo toafford crude(R)-6-cyano-N-(1,1-dimethylethyl)-5-hydroxy-3-oxo-N-(phenylmethyl)hexanamideas an oil.

The oil, approximately 0.1 mol, is dissolved in tetrahydrofuran (150 mL)and methanol (80 mL) under a nitrogen atmosphere. The solution is cooledto -20° C., and a 50% solution of methoxydiethylborane intetrahydrofuran (75 mL) is added. The reaction is cooled to -78° C., andsodium borohydride (12 g, 0.32 mol) is added over 30 minutes. Thereaction is maintained at -78° C. for 5 hours and allowed to warm toroom temperature and stand for 10 hours under a nitrogen atmosphere. Thereaction is quenched by the addition of acetic acid (20 mL) andconcentrated in vacuo to an oil. The residue is dissolved in methanol(300 mL), concentrated by vacuum distillation, redissolved in methanol(200 mL), and reconcentrated in vacuo to give a yellow oil.

The oil is taken up in ethyl acetate (300 mL) and washed with deionizedwater (300 mL). The ethyl acetate solution is concentrated by vacuumdistillation to give crude[R-(R*,R*)]-6-cyano-N-(1,1-dimethylethyl)-3,5-dihydroxy-N-(phenylmethyl)hexanamideas an oil which is as is;

Molecular weight 318. GC/MS m/e 318, 299, 261, 243, 220, 204, 178, 148,106, 91, 65, 57, 41.

The oil, approximately 0.09 mol, is dissolved in 2,2-dimethoxypropane(100 mL, 1.0 mol) and acetone (200 mL). Methanesulfonic acid (0.5 mL) isadded, and the solution is stirred for 2 hours at room temperature. Thereaction is quenched by the addition of aqueous sodium bicarbonate (400mL) and ethyl acetate (300 mL). The ethyl acetate solution isconcentrated in vacuo to give 27.6 g of(4R-cis)-6-(cyanomethyl)-N-(1,1-dimethylethyl)-2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamideas an oil.

A solution of this nitrile (5.0 g, 0.012 mol) in methanol (70 mL)containing anhydrous ammonia (1.05 g) is reacted with hydrogen gas in aParr shaker at 30° C. in a presence of a slurry of Raney nickel A-7000(2.5 g). After 3 hours, uptake of hydrogen has ceased, the mixture iscooled to 20° C., the atmosphere is vented and exchanged for nitrogen,the slurry is filtered through celite, and concentrated in vacuo to give4.2 g of (4R-cis)-6-(2-aminoethyl)-N-(1,1-dimethylethyl)-2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamide as an oil;

Molecular weight 358. GC/MS m/e 358, 343, 301, 287, 260, 243, 227, 204,176, 148, 132, 91, 84, 57, 43.

In a process analogous to Example 1(4R-cis)-6-(2-aminoethyl)-N-(1,1-dimethylethyl)-2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamideis converted to[R-(R*,R*)]-N-(1,1-(dimethylethyl)-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-N-(phenylmethyl)-1H-pyrrole-1-heptanamidewhich is further converted to[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt.

EXAMPLE 6[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt

Preparation of(4R-cis)-1-[[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetyl]piperidine

To a stirred -10° C. solution of 1-acetylpiperidine (127 g, 1.0 mol) intetrahydrofuran (1.0 L) is slowly added a solution of lithiumdiisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) whilemaintaining the temperature between -40° C. to -50° C., and the mixtureis stirred at -20° C. to -30° C. for 30 minutes.(R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g,0.25 mol) as a solution in 200 mL of tetrahydrofuran is then added tothe previous mixture. The reaction mixture is stirred for 30 minutes at-25° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acidsolution (1 L). The aqueous layer is extracted with 500 mL of ethylacetate, the aqueous layer is separated and extracted with 100 mL ofethyl acetate, the extracts are combined and concentrated in vacuo toafford (R)-ε-hydroxy-α,γ-dioxo-1-piperidineheptanenitrile as an oil.

The oil, approximately 0.2 mol, is dissolved in tetrahydrofuran (200 mL)and methanol (100 mL) under a nitrogen atmosphere. The solution iscooled to -20° C., and a 50% solution of methoxydiethylborane intetrahydrofuran (105 mL) is added. The reaction is cooled to -78° C.,and sodium borohydride (24 g, 0.63 mol) is added over 30 minutes. Thereaction is maintained at -78° C. for 5 hours and allowed to warm toroom temperature and stand for 10 hours under a nitrogen atmosphere. Thereaction is quenched by the addition of acetic acid (40 mL) andconcentrated in vacuo to an oil. The residue is dissolved with methanol(400 mL), concentrated by vacuum distillation, redissolved with methanol(300 mL), and reconcentrated by vacuum distillation to give a yellowoil. The oil is taken up in ethyl acetate (300 mL) and washed withdeionized water (500 mL). The ethyl acetate solution is concentrated invacuo to give [ R-(R*,R*)]-γ,ε-dihydroxy-α-oxo-1-piperidineheptanenitrile as an oil which isused as is;

Molecular weight 318. GC/MS m/e 318, 299, 261, 243, 220, 204, 178, 148,106, 91, 65, 57, 41.

The oil, approximately 0.18 mol, is dissolved in 2,2-dimethoxypropane(160 mL, 1.5 mol) and acetone (300 mL). Methanesulfonic acid (0.5 mL) isadded, and the solution is stirred for 2 hours at room temperature. Thereaction is quenched by the addition of aqueous sodium bicarbonate (800mL) and ethyl acetate (500 mL). The ethyl acetate solution isconcentrated in vacuo to give 47.5 g of (4R-cis)-1-[[6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetyl]piperidine as anoil;

Molecular weight 280. GC/MS m/e 280, 265, 240, 222, 205, 182, 164, 154,127, 112, 96, 84, 69, 43, 32.

A solution of the nitrile (5.0 g, 0.017 mol) in methanol (100 mL)containing anhydrous ammonia (1.5 g) is reacted with hydrogen gas in aParr shaker at 30° C. in the presence of a slurry of Raney nickel A-7000(3.8 g). After 3 hours, uptake of hydrogen has ceased, the mixture iscooled to 20° C., the atmosphere is vented and exchanged for nitrogen,the slurry is filtered through celite, and concentrated in vacuo to give4.85 g of(4R-cis)-1-[[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetyl]piperidineas an oil.

In a process analogous to Example 1(4R-cis)-1-[[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetyl]piperidineis converted to[R-(R*,R*)]-1-[3,5-dihydroxy-7-oxo-7-(1-piperidinyl)heptyl]-5-(4-fluorophenyl-2-(1-methylethyl)-N-4-diphenyl-1H-pyrrole-3-carboxamidewhich is further converted to[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt.

We claim:
 1. A process for the preparation of the compound of FormulaI-1 ##STR28## and the dihydroxy acid and pharmaceutically acceptablesalts thereof, corresponding to the opened lactone ring of the compoundof Formula I-1 which comprises:(a) reacting the compound of Formula IVa##STR29## with a compound of Formula V ##STR30## wherein R⁸ or R⁹ isindependently alkyl of from one to ten carbon atoms,cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, benzyl or phenyl or R⁸ and R⁹together are--(CH₂)₄ --, --(CH₂)₅ --, --(CH(R¹⁰)--CH₂)₃ --,--(CH(R¹⁰)--CH₂)₄ --, --(CH(R¹⁰)--(CH₂)₂ --CH(R¹⁰))--,--(CH(R¹⁰)--(CH₂)₃ --CH(R¹⁰))--, --CH₂ --CH₂ --O--CH₂ --CH₂ --,--CH(R¹⁰)--CH₂ --O--CH₂ --CH₂ --, --CH(R¹⁰)--CH₂ --O--CH₂ --CH(R¹⁰)--,wherein R¹⁰ is alkyl of from one to four carbon atoms provided R⁸ and R⁹are not both methyl; and R¹¹ or R¹² is independentlyalkyl of from one tothree carbon atoms or phenyl or R¹¹ and R¹² are taken togetheras--(CH₂)_(n) -- wherein n is 4 or 5 in a solvent to afford a compoundof Formula IIIa ##STR31## wherein R⁸, R⁹, R¹¹, and R¹² are defined asabove; (b) reacting a compound of Formula IIIa with an acid in a solventto afford a compound of Formula IIa ##STR32## wherein R⁸ and R⁹ are asdefined above; (c) (1) hydrolyzing a compound of Formula IIa with abase, (2) followed by neutralization with an acid, and (3) dissolutionand/or heating in a solvent with concomitant removal of water to afforda compound of Formula I-1; (d) and if desired converting the resultingcompound of Formula I-1 to a dihydroxy acid corresponding to the openedlactone ring of structural Formula I-1 by conventional hydrolysis andfurther, if desired converting the dihydroxy acid to a correspondingpharmaceutically acceptable salt by conventional means, and if sodesired converting the corresponding pharmaceutically acceptable salt toa dihydroxy acid by conventional means, and if so desired converting thedihydroxy acid to a compound of Formula I-1 by dissolution and/orheating in an inert solvent.
 2. A process according to claim 1 whereinthe acid in Step (a) is pivalic acid.
 3. A process according to claim 1and for the preparation of(2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.4. A process according to claim 1 and for the preparation of[R-(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, hemi calcium salt.